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Cell Metab. 2011 Apr 6;13(4):428-439. doi: 10.1016/j.cmet.2011.02.013.

Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits.

Author information

1
Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Lund 22184, Sweden.
2
Brain Repair and Imaging in Neural Systems Unit, Department of Experimental Medical Sciences Lund University, Lund 22184, Sweden.
3
Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Center of Molecular Medicine Cologne (CMMC) at the University of Cologne, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) University Hospital Cologne, and Max Planck Institute for Neurological Research, D-50674 Cologne, Germany.
4
Translational Neuroendocrine Research Unit, Department of Experimental Medical Sciences, Lund University, Lund 22184, Sweden. Electronic address: asa.petersen@med.lu.se.

Abstract

In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain.

PMID:
21459327
DOI:
10.1016/j.cmet.2011.02.013
[Indexed for MEDLINE]
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